The likelihood of conceiving diminishes with aging in the human female, but the underlying mechanisms are not understood. This presents a major clinical problem since many women delay childbearing until the 4th and 5th decades of life (e.g., after establishing a career) and existing diagnostic tools cannot reliably predict ovarian reserve which, in turn, is utilized to help determine whether a woman should be treated given her age- associated reduction in reproductive potential. We have previously shown that the pituitary reproductive hormones in older premenopausal women have altered secretory characteristics when compared to younger and older peers. This supports our overall hypothesis that in addition to oocyte depletion and/or abnormal oocyte/follicular interactions, normal aging is associated with detectable changes in the relationships between hypothalamic-pituitary and ovarian hormones, which may be predictive for reduction in ovarian reserve. We propose to further address this hypothesis with a combination of a clinical and mathematical study in younger and older premenopausal women. We will study the effect of aging on the secretion patterns of the ovarian hormones, on the dose-response interactions between pituitary and ovarian hormones and on ovarian feedback on neuroendocrine function. In addition, we will estimate the extent to which these effects can be predicted utilizing some of the existing diagnostic tools. To this end, we will test the specific hypotheses that older premenopausal women compared to their young peers have: 1. Altered secretion characteristics and temporal relationships of the ovarian hormones;2. Reduced ovarian responsivity to neuroendocrine signaling;3. Enhanced gonadal hormones feedback exerted on the neuroendocrine signaling. In addition, we will also test the hypothesis that: 4. Alterations in the pituitary-ovarian endocrine axis associated with normal aging cannot be detected reliably with most of the existing diagnostic tools for estimating ovarian reserve. In contrast to existing studies we will for the first time use interdisciplinary methods to define how aging affects the relationships between the components of the reproductive axis. Identification of such relationships which demonstrate the most robust changes will guide future interventional studies to perform a detailed analysis of the mechanisms of these alterations. Ultimately, our long-term goal is to develop novel diagnostic tools and therapeutic approaches to allow clinicians to make rational decisions regarding which women should or should not be subjected to the various treatment options in connection to age-associated reductions in reproductive potential. PUBLIC HEALTH RELEVANCE: The studies are expected to illuminate the age-related changes in the complex endocrine mechanisms directing the function of the reproductive system. They would allow future studies to focus on the application of this knowledge to develop novel diagnostic and therapeutic approaches to age-associated reductions in reproductive potential.